The investigation of familial Parkinson's disease-related syndromes is likely to provide insight into the pathogenesis of sporadic Parkinsons's disease (PD) and may suggest novel therapeutics. Mutations in the amino-terminal repeat domain of a-Synuclein (alpha-Syn) underlie rare autosomal-dominant, familial forms of PD. Familial, autosomal-recessive mutations in Parkin lead to both juvenile and adult-onset forms of PD. Furthermore, Parkin appears to possess a ubiquitin-ligase activity, implicating it in the protein degradation process. Mounting evidence implicates altered protein ubiquitination and degradation by the ubiquitin/proteasome pathway (UPP) in human neurodegenerative disorders. Both pathological and genetic data link altered protein degradation pathways with PD. A pathological hallmark of PD, the Lewy Body (LB), appears to represent intracellular inclusions composed of multiple proteins including ubiquitin, a-Synuclein (alpha-Syn), ubiquitin carboxy-terminal hydrolase (UCH-L1), and Parkin. Both Parkin and UCH-L1 are implicated in protein ubiquitination, whereas alpha-Syn appears to be a substrate of ubiquitination. The goal of this proposal is to gain an understanding of the mechanisms of action of the PD-related genes alpha-Syn, Parkin. Of particular interest are potential relationships among these molecules. I propose to combine complementary biochemical, cellular, and genetic approaches to this end.